Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disease caused by mutations in the ALDH7A1 gene leading to blockade of the
lysine catabolism pathway. PDE is characterized by recurrent
seizures that are resistant to conventional
anticonvulsant treatment but are well-controlled by
pyridoxine (PN). Most PDE patients also suffer from neurodevelopmental deficits despite adequate seizure control with PN. To investigate potential pathophysiological mechanisms associated with ALDH7A1 deficiency, we generated a transgenic mouse strain with constitutive genetic ablation of Aldh7a1. We undertook extensive biochemical characterization of Aldh7a1-KO mice consuming a low
lysine/high PN diet. Results showed that KO mice accumulated high concentrations of upstream
lysine metabolites including ∆1-piperideine-6-carboxylic
acid (P6C), α-aminoadipic semialdehyde (α-AASA) and
pipecolic acid both in brain and liver tissues, similar to the biochemical picture in ALDH7A1-deficient patients. We also observed preliminary evidence of a widely deranged
amino acid profile and increased levels of
methionine sulfoxide, an oxidative stress
biomarker, in the brains of KO mice, suggesting that increased oxidative stress may be a novel pathobiochemical mechanism in ALDH7A1 deficiency. KO mice lacked epileptic
seizures when fed a low
lysine/high PN diet. Switching mice to a high
lysine/low PN diet led to vigorous
seizures and a quick death in KO mice. Treatment with PN controlled
seizures and improved survival of high-
lysine/low PN fed KO mice. This study expands the spectrum of biochemical abnormalities that may be associated with ALDH7A1 deficiency and provides a proof-of-concept for the utility of the model to study PDE pathophysiology and to test new
therapeutics.